Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer that is characterised by impressive initial response rates to platinum-based chemotherapy, followed by nearly universal relapse with platinum-resistant disease. Whilst some mechanisms of resistance have been identified, there has been a lack of comprehensive unbiased screening to survey mechanism of resistance in SCLC. To address this, we employed an unbiased whole-genome gain-of-function screening approach using CRISPR activation (CRISPRa) to identify genetic drivers of platinum resistance. As a proof of concept, we identified genes associated with glutathione metabolism which has previously been associated with platinum resistance. These genes include solute carrier family 7 member 11 (SLC7A11), a known facilitator of cellular cystine uptake which contributes to glutathione biosynthesis. Here we demonstrated that 1) SLC7A11 overexpression enhances resistance to platinum agents in SCLC cell lines, 2) expression of SLC7A11 is upregulated in platinum-resistant SCLC cell lines, and 3) treatment with platinum in combination with a SLC7A11 inhibitor, sulfasalazine, is efficacious in vitro. In addition, we have identified genes controlling biological processes that have not been previously linked to platinum sensitivity which we are currently investigating with the aim of identifying new therapies to overcome platinum resistance in this devastating disease.